9 halo-21-fluoro-steroids of the pregnane series



nited States Patent 3,042,690 9 HALO-Zl-FLUORO-STEROIDS OF THE PREGNANESERIES Josef Fried, Princeton, NJ., and Josef E. Herz, Lomas,

Mexico, assignors to Olin Mathieson Chemical Corporation, New York,N.Y., a corporation of Virginia No Drawing. Filed May 26, 1960, Ser. No.31,825

4 Claims. (Cl. 260-397 .45)

This application is a continuation-in-part of our parent applications,Serial No. 583,934, filed May 10, 1956, now Patent No. 2,973,376,granted February 28, 1961, and Serial No. 585,155, filed May 16, 1956,now Patent No. 2,973,356, granted February 28, 1961.

This invention relates to the synthesis of valuable steroids and has forits objects the provision of new steroids of the pregnene series; havinga fluoro substituent in the 21-position, a halogen substituent in the9a-position, and either a B-hydroxy or keto substituent in thell-position.

The novel steroids of this invention can be represented by the generalformula:

wherein Y is hydrogen or a-methyl; R. is hydrogen, R is B-hydroxy, ortogether R and R is keto; and X is halogen.

Representative steroids preparable by the process of this inventioninclude: 90:112110-21-1111010-1 1,8, 17 a-dihydroxyprogesterones (i.e.9a,2l-difluoro-11,9,17a-dihydroxyprogesterone, 9a-chloro-Zl-fluoro-l1B,l7a-dihydroxyprogesterone, 9a bromo-21-fiuoro-115,17u-dihydroxyprogesterone and 9a-i0d0-9a-halo-2l-fluoro-11-keto 17a hydroxyprogesterones 9a,21-difluoro-11keto 17a hydroxyprogesterone,9achloro-2l-fluoro-1l-keto-17a-hydroxyprogesterone,9ozbromo-21-fluoro-11-keto-17a-hydroxyprogesterone, and9oc-i0dO-2l-fl1l0l'O-1 l-keto-l7a-hydroxyprogesterone)2-rnethyl-9u-halo-2l-fluoro-l1,8,17a dihydroxyprogesterones (i.e.

2-methy1-9a,21-difiuoro-l1,8,17a dihydroxyprogesterone,

2-methyl-9a-chloro-2 l-fiu'oro-l 1,3, 17udihydroxyprogesterone,2-methyl-9a-bromo-2l-fluoro 115,170: dihydroxyprogesterone and2-methyl-9a-iodo-2l-fiuoro-l1p, 17 m-dihydroxyprogesterone), and

2-methyl-9u-halo-21-fiuoro-1l-keto-17a hydroxyprogesterones (e.g.,

2-rnethyl-9a,2l-difiuoro-ll-keto 171x hydroxyprogesterone and2-methyl-9u-chloro-2l-fluoro-l1-keto-17a-hydroxyprogesterone) To preparethe 21-fluoro compounds of this invention, a steroid of the generalformula:

lce

GHzOH o R ----on wherein Y, R, R, and X are as hereinbefore defined, isreacted with an alkanesulfonyl halide. Representative steroids suitableas initial reactants in the process of this invention include9a-halohydrocortisones (i.e., 9a-flu0rohydrocortisone,9a-chloro-hydrocortisone, 9o: brornohydrocortisone and9a-iodohydrocortisone), 9a-halocortisones (i.e., 9a-fluorocor-tisone,9a-chloroco-rtisone, 9oz- -bromocortisone and 9a-iodocortisone),2-methyl-9a-halohydrocortisones (i.e., 2-methyl-9a-fluorohydrocortison2-methyl-9ct-chlorohydrocortisone, 2-methyl-9u bromohydrocortisone, and2-methyl-9a iodohydrocortisone), and 2-methyl-9a-halocortisones (e.g.,2-methyl-9a-fluorocortisone and 2-methyl-9a-chlorocortisone).

These steroids are reacted with an alkanesulfonyl halide (sulfonylchlorides are preferred, but other halides such as bromides and iodidesmay be used). Although any alkanesulfonyl chloride may be used, thealkane group is preferably a lower alkane, methanesulfonyl chloride(mesyl chloride) being particularly preferred. The reaction is carriedout by intermixing the steroid and sulfonyl halide under substantiallyanhydrous conditions and preferably in the cold (e.g., at a temperatureless than about 20 C.) in the presence of pyridine or other organicbase.

The reaction results in the production of intermediate steroidscontaining in the 21-position and alkanesulfonyloxy radical whichcorresponds to the alkanesulfonyl halide used in the reaction. Thepreferred intermediate 21- alkanesul fonyloxy compounds are those of thefollowing general formula:

wherein R" is alkyl (preferably lower alkyl) and Y, R, R and X are ashereinbefore defined.

These 21-alkanesulfonyloxy intermediates are then reacted with an alkalimetal fluoride (particularly potassium fluoride) in an organic solventof high dielectric constant, such as dimethylformamide ordimethylsulfoxide. This reaction is preferably, but not necessarily,conducted at elevated temperature, a temperature range of l00- C. beingpreferred. The reaction yields the 21-fluoro final products of thisinvention.

If the starting steroid contains an llp-hydroxy group, and an ll-ketosteroid is desired as the final product, the former can be oxidized inthe usual manner, as by treating with a hexavalent chromium compound(e.g., chromic acid) in an acid medium (e.g., glacial acetic acid).

The steroids of this invention are physiologically active steroids whichpossess glucocorticoid activity. Thus, the

' 3 new steroids of this invention can be administered instead of, andin the same manner as, cortisone or hydrocortisone in the treatment ofrhumatoid arthritis and dermatomyositis. The dosage for suchadministration is, of course, dependent on the relative activity of thecompound.

The following examples are illustrative of the invention (alltemperatures being in Centigrade):

EXAMPLE 1 9a-21-Diflzloro-A -Pi egnene-l 1B,17a-Di0l-3,20-Di0ne To asolution of 200 mg. of 9a-fluorohydrocortisone 21- mesylate in 5 ml. ofredistilled dimethylformamide is i properties: M.P. about 259-261"; [cc]+147 (c, 0.3

in dioxane), +134 (c, 0.53in acetone);

N3; 239 m (e=16,400),

mu 2.89m 3.641;, 5.84;, 6.01-6.95

Analysis.--Calcd. for C H O F (382.43): C, 65.95; H, 7.38; F, 9.94.Found: C, 65.96; H, 7.43; -F, 9.87.

I 9a,2l-difiuoro-M-pregnened1,8,17a-diol-3,20-dione possesses about fiveto seven times the activity of cortisone acetate in the liver glycogenassay.

Upon concentration of the chloroform solution, from which the insoluble2l-fluoro compound has been removed, in vacuo and recrystallization oftheresidue from 95% ethanol, there is obtained a product having thefollowing properties: M.P. about 272274; [a] l162 (c, 0.57 inchloroform); tile. 237 m (e=l8,300);

Analysis.Calcd. for 1-1 0 (362.43): C, 69.61; H, 7.51; F, 5.37. 'Found:C, 69.77; H, 7.77; F, 5.65.

The procedure of Example 1 can be conducted with dimethylsulfoxideinstead of dimethylformamide to give the same results.

To a solution of 100 mg. of 9a,2l-difluoro-M-pregnene-11,3,17Ct-di0l-3,20-dl0fl in ml. of glacial acetic acid is EXAMPLE 39d-Chl0r0-21-Flu0r0-A Pregnene-11[3,1 7a- Dial-3,20-Dione Following theprocedure of Example 1, but substituting 200 mg. of9a-chloro-hydrocortisone Zl-mesylate for the Qa-fiUOI'O-hYdl'OCOItiSOYlG2l-mesylate, 9a-chloro-2l-fluoro- Mpregnen -l 16,17 a-diol-3,20-dione isobtained.

EXAMPLE 4 Qa-Bromo-Z] -Flu0r0-A -Pregnene-1 1 5,1 7a-Di0l- 3 ,ZO-D ioneFollowing the procedure of Example 1, but substituting 200' mg. of9oc-bromo-hydrocortisone 21-mesylate for the 9a-fiuoro-hydrocortisone2l-mesylate, 9a bromo 2lfluoro-A -pregnene-l1B,l7a-diol-3,20-dione isobtained.

EXAMPLE 5 9a-I ado-21 -Flu0r0-A -Pregnene-115,1 7a-Di0l-3,20-DioneFollowing the procedure of Example 1, but substituting 200 mg. of9u-iodo-hydrocortisone 21-mesy1ate for the 9a-fluoro-hydrocortisone2l-mesylate, 9a-iodo-21-fluoro- A -pregnene-1l,8,17oc-diol-3,20-dione isobtained.

EXAMPLE 6 Following the procedure of Example 2, but substituting9a-chloro-2l-fluoro-M-pregnene-11B,l7a-diol-3,20 dione for the steroidreactant in that example, there is obtained diol-3,20-dione and9u-iodo-21-fiuoro-A -pregnene 11B,

l7a-diol-3,20-dione can be converted to Qoc-bIOIIlO-Zlfiuoro-A-pregnene- 1711-01-3, 1 1,20-trione, respectively.

EXAMPL 7 9a,21 -Diflu0r0-2-M ethyl-1 I 5.1 7a-Dihydroxyprogesterone (a)Preparation of 9a-fluoro-2-methylhydrocortisone 2l-mesylate: To asolution of 13 mg. of 9a-fiuoro-2- methylhydrocortisone in 0.5 ml. ofanhydrous pyridine is added at 0, 0.05 ml. of methanesulfonyl chloride.After 2.5 hours at 0, water is added and the'resulting mixture isextracted with dilute hydrochloric acid, dilute sodium bicarbonate andwater. The chloroform extract is dried over sodium sulfate andevaporated to dryness in vacuo. The residual syrup representsessentially pure 9a-fiuoro- Z-methylhydrocortisone 21-mesylate and isused in the process of Step 12 without further purification.

(b) Preparation of 9a,21-difiuoro-2- methyl-l 15,1701-dihydroxyprogesterone: A mixture containing 100 mg. of9a-fluoro-Z-methylhydrocortisone mesylate and 100 mg. of anhydrouspotassium fluoride in 4 ml. of freshly distilled dimethylfor-mamide isheated under nitrogen at 110 for 17 hours. After removal of the bulk ofthe solvent in vacuo, the mixture is takenup in water and chloroform,the chloroform solution washed with water, dried over sodium sulfate andthe solvent removed in vacuo. The residual solid is then recrystallizedfrom 95% alcohol.

Similarly, by substituting an equivalent amount of9achloro-Z-methylhydrocortisone,9a-bromo 2 methylhydrocortisone and9a-iodo-2-methylhydrocortisone for the 9u-fiuoro2-methylhydrocortisonein Stop a of Example 7 and following the procedure of the example, thecorresponding 9a-chloro, t-b1'OmO and 9a-iodo derivatives are formed,respectively.

EXAMPLE 8 9a,21 -Difluoro-2-M ethyl-1 1 -Ket0-1 7 oi-Hydroxyprogesterone To a solution of 25 mg. of9a,2l-difluoro-2-methyl-l1B, l7u-dihydroxyprogesterone in 2 ml. ofglacial acetic acid is added over a period of 15 minutes a solution of12 mg. of chromic acid in 2 ml. of acetic acid. Aften an addi tional 10minutes at room temperature, 0.2 ml. of alcohol is added to destroyexcess chromium trioxide and the solution concentrated in vacuo to smallvolume. The residual syrup is distributed between chloroform and water,and the chloroform solution washed with water, dilute sodium bicarbonatesolution and again with water. After drying over sodium sulfate, thesolvent is removed in vacuo and the crystalline residue consisting of9a,21-difloro-2- methyl-l l-keto-l7u-hydroxyprogesterone 1'srecrystallized from ethanol.

The invention may be otherwise embodied within the scope of the appendedclaims.

5 What is claimed is: 1. A steroid of the general formula:

wherein, R is hydrogen, R is fi-hydroxy and together R and R is Kate,and X is halogen.

2. 9a-ha1o-21-fluoro-1 1,8, l7a-dihydroxyprogesterone. 3.9a-ha1o-21-fluoro-17a-hydroXy-11-ketoprogesterone. 5 4.9a,21-difluoro-111S,17a-dihydroxyprogesterone References Cited in thefile of this patent UNITED STATES PATENTS 10 3,005,837 Lincoln et a1.Oct. 24, 1961

1. A STEROID OF THE GENERAL FORMULA: